Can a bone marrow transplant really affect psychotic symptoms in schizophrenia?

"Though BMT [bone marrow transplantation] may not be a cure for all cases of schizophrenia, it definitely possesses the potential to manage overall disease severity and improve the quality of life, and this case report is a preliminary demonstration of the safety and efficacy of BMT in treatment-resistant schizophrenia."

So said the findings reported by Tsuyoshi Miyaoka and colleagues [1] (open-access available here) discussing a case report of a young man initially diagnosed with paranoid schizophrenia which was eventually deemed 'treatment-resistant' on the basis of his lack of [positive] response to anti-psychotic medication(s) given for "his auditory hallucinations, suspiciousness, active social avoidance, persecutory delusion, and deterioration in the level of social functioning."

Things unfortunately got worse for this young man we are told, as he was subsequently diagnosed with acute myeloid leukemia - cancer of the white blood cells - setting in motion the initially daunting task of treatment via a bone marrow transplant. As the name suggests, BMT involves the transplantation of bone marrow where stem cells are made. Stem cells are those wonderful cells that give rise to the various types of blood cells we all have among other things. The idea being that a kinda of reboot of white blood cells in this case could potentially treat his leukemia.

Although Miyaoka et al don't actually say how successful the BMT was for his leukemia (the patient was alive 8 years after BMT so I assume successful), they do talk about what happened to his psychotic symptoms following the BMT. So: "Thirty days later, his psychotic symptom had almost disappeared. He was sustained without any neuroleptic treatment and need for any other administration." Indeed, this didn't appear to be any short-term effect neither as "8 years after BMT, the improvements of somatic and psychiatric symptoms are continued, and the patient is very well and there are no residual psychiatric symptoms." In short, things were still going well for this young man both in terms of his past leukemia diagnosis and also psychotic symptoms.

There is always the possibility of "spontaneous improvement without any treatment" as accounting for the psychiatric results presented by the authors. Indeed, I also note that various immunosuppressive medicines were also administered around the time of the BMT to "avoid graft versus host disease (GVHD)" which might also have played some role in light of other research suggestions [2]. One has to be careful not to jump to too many conclusions particularly on the basis of single case reports.

But... it is a potentially important coincidence that use of a BMT came at the same time as the symptom changes noted. I'll also draw your attention to a 'call for case histories' on the topic of "BMT in patients with coincident schizophrenia" made by Sommer and van Bekkum [3] on the back of other work from these authors in relation to "the possibility that schizophrenia may be transmitted" where "a patient... developed severe psychosis after receiving a BM transplant from his schizophrenic brother" [4]. It seems that there may be a two-way process potentially at work when it comes to immune function and schizophrenia.

This is interesting stuff. Framed alongside the idea that schizophrenia might not be a homogeneous condition - think 'the schizophrenias' -  and that at least one 'type' of schizophrenia might have a significant 'immune' component to it (see here for example), one could envisage further investigations on the potential use of BMT in certain cases. I do have to mention safety and the possible side-effects of BMT outside of just GVHD (see here) as being important considerations; added to the invasiveness of BMT.

And whilst we're on this topic, I'd also direct you to some chatter about mice and bone marrow transplants in the context of autism some years back (see here) minus any sweeping generalisations but again, interesting...

----------

[1] Miyaoka T. et al. Remission of Psychosis in Treatment-Resistant Schizophrenia following Bone Marrow Transplantation: A Case Report. Front Psychiatry. 2017 Sep 21;8:174.

[2] Knight JG. et al. Rationale for a trial of immunosuppressive therapy in acute schizophrenia. Mol Psychiatry. 2007 May;12(5):424-31.

[3] Sommer IE, van Bekkum DW. Call for case histories of BMT in patients with coincident schizophrenia. Bone Marrow Transplantation. 2013;48(6):880.

[4] Sommer IE. et al. Severe chronic psychosis after allogeneic SCT from a schizophrenic sibling. Bone Marrow Transplantation. 2015;50(1):153-154.

----------

"a gluten-related subgroup of schizophrenia"?

A quote to begin this post: "this preliminary study demonstrates that altered AGDA [antibodies against gliadin-derived antigen] levels in the circulation are associated with schizophrenia and could serve as biomarkers for the identification of a schizophrenia subgroup that may need an alternative therapy or precision treatment."

So said the findings reported by McLean and colleagues [1] (open-access) looking at an area of some interest to this blog (see here) on how dietary gluten might show something of an important relationship to at least some cases of schizophrenia. Just in case you weren't aware, there is quite a history when it comes to gluten and schizophrenia (see here) as per the very forward-thinking of people such as Curt Dohan and Karl Reichelt.

Researchers on this latest occasion set about looking in a little more detail at the suggestion that circulating anti-gliadin antibodies (AGAs) reflective of an immune response to a component of dietary gluten might show some connection to schizophrenia. Indeed they note that "all the tests for circulating AGAs in schizophrenia have been developed with mixtures of full-length native gliadins consisting of ~300 amino acid residues" suggesting that such a scatter gun approach may have included epitopes "that are unlikely to survive digestion in the gut." So, they instead "measured plasma levels of IgG and IgA against indigestible peptide fragments derived from γ- and α-gliadins" in archived plasma samples from "169 patients with schizophrenia and 236 control subjects."

The results - based on the use of an "In-house ELISA for antibodies against gliadin-derived antigens" - were rather intriguing. So: "There was no significant difference in the levels of plasma antibodies against native gliadins between the patient group and the control group." If I'm reading this right, this finding is in contrast to other independent research occasions [2]. Indeed, when it came to looking at both IgA and IgG plasma anti-gliadin antibodies, there was no significant difference between the schizophrenia and non-schizophrenia participants as groups.

But... when it came to a specific gliadin (γ-Gliadin) derived fragment  - AAQ6C - with the amino acid sequence HPKCSIMRAPFASIVAGIGGQYRD - researchers reported on something potentially important to see: "patients with schizophrenia had significantly higher levels of plasma anti-AAQ6C IgG than control subjects." Importantly too, authors also noted that anti-psychotic medication did not appear to influence their antibody results. This was important given that seemingly all of the participants diagnosed with schizophrenia were taking one or more of this class of medicine. In line with the opening quote to this post, the authors make a preliminary foray into the possible 'biomarker' usefulness of the various anti-gluten antibodies for schizophrenia. I have to say on this point however, that the data is not that impressive as things currently stand.

There is more to do when it comes to the possible effects of dietary elements containing gluten (and casein) in relation to cases of schizophrenia. This work adds something to the idea that diet can affect psychiatry/behaviour/development but what is perhaps missing is the recognition that schizophrenia is probably a heterogeneous and plural condition (see here and see here for examples) and as such, not every case is going to be gluten and/or casein-related. I do agree with the authors that more research is needed in this area alongside the idea that intervention via either dietary changes [3] and/or other options might also be on the research agenda...

----------

[1] McLean RT. et al. Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational Psychiatr. 2017. May 9.

[2] Dickerson F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):100-4.

[3] Jackson J. et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophrenia Res. 2012;140(0):262-263.

----------

McLean RT, Wilson P, St Clair D, Mustard CJ, & Wei J (2017). Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational psychiatry, 7 (5) PMID: 28485731

B vitamins for schizophrenia?

I'd like to briefly draw your attention to the results - systematic review and meta-analysis results - published by Joseph Firth and colleagues [1] observing that "certain vitamin and mineral supplements may reduce psychiatric symptoms in some people with schizophrenia" and specifically that certain B vitamins might be something to consider.

Such results come from a research team who are making significant waves in the field of meta-analyses and systematic reviews for all manner of different [important] topics. The additional inclusion of one Jerome Sarris to the authorship team adds a 'nutritional medicine as mainstream in psychiatry' touch to proceedings.

Drawing on data from 18 clinical trials - randomized controlled trials (RCTs) - cumulatively including over 800 participants, researchers reported that: "vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms significantly more than control conditions." Dose seemed to be important (higher doses appeared to be more effective than lower doses) as did timing of vitamin 'intervention'. Authors also indicated that subgroups of people with schizophrenia might be 'better responders' to this type of intervention, suggesting that either individual genetic differences or possibly nutritional deficiency before intervention might count in terms of effectiveness of B vitamin use. I was wondering whether those last points might tie into other discussions on this blog referencing genotype, B vitamins and [some] schizophrenia (see here).

In the context of the rise and rise of plurality in psychiatry ('the schizophrenias' and 'schizophrenia does not exist: discuss') there are some important research directions to be followed on the basis of the Firth findings. Identifying those people on the schizophrenia spectrum who might be potential best responders to this type of nutritional intervention is a research priority. Closely followed by further investigations on the hows-and-whys of such intervention potentially being useful. In that final respect, the peer-reviewed literature has already provided a few ideas for starters (see here and see here for examples).

To close, "I've got a good idea..."

----------

[1] Firth J. et al. The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychological Medicine. 2017. Feb 16.

----------

Firth J, Stubbs B, Sarris J, Rosenbaum S, Teasdale S, Berk M, & Yung AR (2017). The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychological medicine, 1-13 PMID: 28202095

Psychosis (sometimes) as an immune disorder?

"Some psychosis cases an 'immune disorder'" went the BBC headline with reference to the paper by Belinda Lennox and colleagues [1] talking about the detection of antibodies against the N-methyl-D-aspartate receptor (NMDAR) in cases of first-episode psychosis (FEP).

Although by no means a universal phenomenon, researchers reported that 3% of their 228 participants diagnosed with FEP who provided a blood sample showed the presence of NMDAR antibodies compared with none of the healthy controls (n=105) included for study. As part of the condition known as anti-NMDAR encephalitis, the presence of NMDAR antibodies can indeed include/induce psychotic features [2].

This is interesting work. For anyone that has come across the book 'Brain on Fire' by Susannah Cahalan, there is a growing interest in how the presentation of psychiatric features can, on occasion, include a significant role for the immune system and particularly, the concept of autoimmunity (where the body's own immune system fails to differentiate between 'self' and 'other'). Some of the authors included on the Lennox paper have previously summarised and discussed the idea that NMDAR antibodies might show a connection to some cases of psychosis and conditions manifesting psychosis such as schizophrenia [3]. The current data tally with their previous conclusion that: "A minority of patients with psychosis are anti-NMDA receptor antibody positive" and onwards the idea that there may be many different 'roads' to psychosis in these days of plural conditions (see here).

Where next for this research area I hear you ask? Well, set against the idea that various autoimmune diseases might be over-represented alongside a diagnosis like schizophrenia (see here), one needs to tease out some of the hows-and-whys details. Does, for example, a history of autoimmune disease 'set someone up' for psychosis and/or schizophrenia? Or is the autoimmune element of it something that follows a diagnosis of psychosis and/or schizophrenia? I have some opinions on this based on other findings on how autoimmunity may come about for some (see here for some discussion on HERVs) taking into account other peer-reviewed ideas and data [4]. I don't profess to be right or offer any universal answer but it is interesting that endogenous virus expression does seem to be heightened in a condition like schizophrenia and said elements might be considered important in processes such as molecular mimicry as one mechanism of autoimmunity [5]. There is a research plan to carry out and specifically on the topic of how NMDAR antibodies come about.

The other important 'where next' for this area of investigation is the tantalising prospect that 'treating' said autoimmune reaction might have some important effects on the presentation of something like FEP. There are hints out there in the peer-reviewed literature of possible treatment options being available. I might for example, draw your attention to some overlapping work looking at anti-NMDAR encephalitis ('encephalitis' that is) and cases of autism (see here and see here) where intervention options are discussed. With no medical advice given or intended, methylprednisolone seems to have found therapeutic favour for some. Other, more aggressive treatment options have also been reported but further investigations are required.

I note the words 'immuno-psychiatry' are mentioned in the media reporting of the Lennox findings and I'm happy to see the profile of this area of research being elevated through such work. The idea that immune function(s) might be doing so much more than just identifying and eradicating foreign bodies to maintain our physical health continues to gather pace...

----------

[1] Lennox BR. et al. Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. Lancet Psychiatry. 2016. Dec 7.

[2] Dalmau J. et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurology. 2011;10(1):63-74.

[3] Pollak TA. et al. Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychol Med. 2014 Sep;44(12):2475-87.

[4] Slokar G. & Hasler G. Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia. Frontiers in Psychiatry. 2015;6:183.

[5] Trela M. et al. The role of molecular mimicry and other factors in the association of Human Endogenous Retroviruses and autoimmunity. APMIS. 2016 Jan-Feb;124(1-2):88-104.

----------

Lennox, B., Palmer-Cooper, E., Pollak, T., Hainsworth, J., Marks, J., Jacobson, L., Lang, B., Fox, H., Ferry, B., Scoriels, L., Crowley, H., Jones, P., Harrison, P., & Vincent, A. (2016). Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study The Lancet Psychiatry DOI: 10.1016/S2215-0366(16)30375-3

C-reactive protein "may be a causal risk factor for schizophrenia"

Although the public perception of science is that researchers go around 'proving' or 'disproving' that A leads to B or X causes Y, it is still surprisingly rare to see the word 'causal' in many areas of peer-reviewed research. Aside from the fact that science generally works around the concept of 'probability' - producing data pertinent to discussions on whether something is more or less likely to be true/false - most science is not so forthright in its conclusions. Certainly science covering the area of behaviour and medicine tends to be a little more 'shades of grey' than anything else when it comes to causality...

When I therefore see research articles talking about 'causality' particularly in the domain of psychiatry and behaviour, they tend to grab my attention. So it was when I stumbled across the paper by Masatoshi Inoshita and colleagues [1] (open-access) who, and I quote, reported that their cumulative findings "suggest that elevated CRP itself may be a causal risk factor for schizophrenia."

CRP refers to C-reactive protein, a pentraxin produced in the liver that "rises when there is inflammation throughout the body." In these days of layer upon layer of experimental evidence indicating that immune function may play an important role in psychiatry and behaviour (see here), it is not surprising to see a marker of systemic inflammation being linked to a complicated condition like schizophrenia given what research has already said about such a connection (see here).

The Inoshita study was an interesting one insofar as it represented yet another 'value-added' study where researchers first produced their own data on the topic and then undertook a meta-analysis on the topic of CRP and schizophrenia. I've covered such a method on at least two other occasions on this blog (see here and see here).

The first part of their study found that: "The mean serum CRP levels in the 408 patients with schizophrenia and the 1,247 control subjects were 0.36 mg/dl (SD = 0.81) and 0.03 mg/dl (SD = 0.01), respectively" = it was elevated in the schizophrenia group. Analysis was also undertaken taking into account genetics potentially affecting levels of CRP where "2 common SNPs... (rs2794520 in the CRP gene and rs1183910 in the HNF1 homeobox A (HNF1A) gene) were selected." Part of this included a Mendelian randomization analysis, the results of which [partially] "provided evidence for a causal association between elevated CRP levels and schizophrenia risk."

A meta-analysis was also carried out "of previous case-control studies between serum CRP levels and schizophrenia." Based on data from 14 case-control studies including "a total of 1,664 patients with schizophrenia and 3,070 control subjects", researchers found that "serum CRP levels were significantly higher in patients with schizophrenia than in the controls" (although with "significant heterogeneity among studies"). Cumulatively, they concluded, there is something to see when it comes to CRP and schizophrenia; indeed: "Our finding suggests that CRP levels are causally associated with not only late- and very-late-onset schizophrenia but also general schizophrenia."

From all the topics that I've covered on this blog, the association between elevated CRP and schizophrenia is perhaps one of the strongest insofar as the amount and direction of data/evidence that has been produced and documented; also crossing different geographies. Accepting that it may be slightly problematic to use the term 'schizophrenia' in these days of pluralised labels (see here) and that there may be 'outliers' ("we excluded from our association study any subjects who had a CRP concentration below the assay’s limit of 0.02 mg/dl (a total of 127 subjects; patients N = 9, controls N = 118)"), the time has surely come to start treating such data seriously. Not least because if higher levels of CRP are present, there may be ways and means to reduce them and potentially also impact on the presentation of symptoms. The authors seem well aware of this point: "several clinical studies have demonstrated the efficacy of anti-inflammatory drugs, such as aspirin and the cyclooxygenase-2 (COX-2) inhibitor celecoxib, on the symptoms in patients with schizophrenia" (with no medical or clinical advice given or intended).

I don't however doubt that CRP is merely one facet of quite a lot of schizophrenia (see here) nor that it is not a condition specific finding (see here and see here). That other pentraxins may also be linked to immune functions in cases of schizophrenia is also potentially important (see here) as are the multitude of other molecular targets that have been reported on down the years with an immune system feel to them [2].

The use of Mendelian randomization where "genetic variants that either alter the level of, or mirror the biological effects of, a modifiable environmental exposure that itself alters disease risk should be related to disease risk to the extent predicted by their influence on exposure to the environmental risk factor" seems to be in the research ascendancy these days as per other examples where important biological variables have been linked to something like schizophrenia [3]. I like the idea of what this statistical technique can bring but would perhaps take exception to the sole focus on structural genetics at the expense of other issues potentially affecting gene expression. That also it is not outside the realms of possibility that there may be a coincidence of factors linking something like CRP and vitamin D mentioned in the paper by Taylor and colleagues [3] is something else to consider (see here).

But, yet again, with CRP we have something testable and quantifiable to measure and potentially act upon where values fall outside of accepted reference ranges...

----------

[1] Inoshita M. et al. A significant causal association between C-reactive protein levels and schizophrenia. Sci Rep. 2016 May 19;6:26105.

[2] Chase KA. et al. The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia. BMC Psychiatry. 2016; 16: 152.

[3] Taylor AE. et al. Investigating causality in the association between 25(OH)D and schizophrenia. Sci Rep. 2016 May 24;6:26496.

----------

Inoshita M, Numata S, Tajima A, Kinoshita M, Umehara H, Nakataki M, Ikeda M, Maruyama S, Yamamori H, Kanazawa T, Shimodera S, Hashimoto R, Imoto I, Yoneda H, Iwata N, & Ohmori T (2016). A significant causal association between C-reactive protein levels and schizophrenia. Scientific reports, 6 PMID: 27193331

“Schizophrenia” does not exist. Discuss.

With a title like "“Schizophrenia” does not exist", the opinion piece by Jim van Os [1] (open-access) was bound to attract some attention and comment (indeed, several). As per other examples where diagnostic labels have been questioned (see here) the response to such viewpoints typically falls into one of two categories: (a) the person or persons making the suggestion just want to make a name for themselves (and how better than to stir up a bit of controversy) or (b) the person or persons making the claim have a valid point.

In the case of the viewpoint posited by van Os, and without trying to offend too many people, I'm tending towards the latter option because I think he has a point. Read onwards and I'll try and explain why.

The crux of the suggestion is that in these days of increasing pluralisation of diagnostic labels (see here for another example) and realisation that individual behavioural or psychiatric labels rarely occur unaccompanied (see here) the idea that there is a discrete condition called schizophrenia is fast losing 'evidence-based' backing. His descriptions of how DSM-5 classifies schizophrenia and the various diagnostic classifications that patients may 'move in and out of', harks back to some of the reasons why the RDoC (Research Domain Criteria) initiative was first suggested and continues to gather momentum.

As per other entries on this blog acknowledging the idea of the more plural 'schizophrenias' (see here) and even a 'bipolar - schizoaffective - schizophrenia spectrum' (see here), van Os suggests a more wide-ranging term to supplant schizophrenia: psychosis spectrum syndrome. This label, it is suggested, takes account of the "extreme heterogeneity, both between and within people, in psychopathology, treatment response, and outcome." van Os also suggests that the creation of such a spectrum is a way to "forget about “devastating” schizophrenia as the only category that matters and start doing justice to the broad and heterogeneous psychosis spectrum syndrome that really exists."

I don't believe we're going to see a dramatic migration towards psychosis spectrum syndrome as a replacement for the singular schizophrenia term very quickly. Much like what goes on behind other conditions/labels, change is often a slow process in medicine and convincing people who might have their own reasons for sticking with the label schizophrenia (e.g. identity, management options, etc.) will prove difficult. That we already have a similarly worded term, [unspecified] schizophrenia spectrum disorder in the current manifestation of DSM is an additional point of complication to make.

Still, I can see the benefits of taking a wider approach to the categorisation of symptoms in this area of psychiatry. Indeed, if one considers the data on schizophrenia spectrum disorder appearing alongside 22q11.2 deletion syndrome for example (see here) you get a flavour for how many routes there may be taking someone towards clinically significant symptoms. That 'treatment response' may also guide the appreciation of a wider spectrum definition encompassing schizophrenia (see here for example), one could foresee a time when a specific place on the psychosis spectrum is given to patients and the trial-and-error of symptom management potentially becomes a thing of the past with the right patient work-up. That is also assuming some accuracy in [some of] the management options put forward [2]...

That all being said, in agreement with this article by Allen Frances on a related topic, I think we also have to be a little careful not to be too broad in our brush strokes on spectrum generalisations.

Music: War and Low Rider.

----------

[1] Os van J. "Schizophrenia" does not exist. BMJ. 2016 Feb 2;352:i375.

[2] Jauhar S. et al. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. Br J Psychiatry. 2014 Jan;204(1):20-9.

----------

Os, J. (2016). “Schizophrenia” does not exist BMJ DOI: 10.1136/bmj.i375

22q11.2 Deletion Syndrome and 'a highly increased risk of schizophrenia spectrum disorders'

22q11.2 deletion syndrome has turned out to be something of real interest to this blog. Not only because of the reported connection to the presentation of autism (see here) including some suggestion of a role for the immune system (see here) but also because of the idea that certain somatic comorbidity linked to the gastrointestinal (GI) tract might also figure as part of the presentation of at least some cases of Del22 (see here). Said GI issues have also cropped up across quite a few other labels including cases of autism.

One of the other important psychiatric comorbidities suggested to be over-represented where Del22 is present is that of schizophrenia and related conditions. Indeed, a recent paper by Anders Vangkilde and colleagues [1] confirms that: "Carriers of a 22q11.2 deletion who had been clinically identified had a highly increased risk of schizophrenia spectrum disorders."

Based on the analysis of data from one of those oh-so-grand Scandinavian nationwide registers (in this case based in Denmark), researchers identified just over 150 people diagnosed with 22q11.2 deletion syndrome. Further inspection of those carrying the 22q11.2 deletion revealed that "6 individuals were diagnosed with schizophrenia spectrum disorders." Although seemingly only a small number, the calculated risk of schizophrenia spectrum disorder (SSD) occurring alongside Del22 was judged to be quite a bit higher than when Del22 is not present: "an 8.13(95% CI: 3.65-18.09) fold increased risk."

Schizophrenia and related conditions appearing alongside Del22 is not new news. Quite a bit of peer-reviewed literature has been generated on this topic including the idea that there may be changes to cognitive skills preceding the development of a psychotic illness [2]. Such evidence has obvious repercussions for issues such as preferential screening and the like, but perhaps just as importantly is the idea that such an association might carry important information on the mechanism pertinent to at least some types of SSD. Take for example the findings reported by Monks et al [3] who, alongside reporting that psychotic illness was present in approaching a third of their cohort with Del22 also suggested that: "Psychosis proneness seems to be of genetic origin in 22q11.2DS" on the basis of their comparing features with "non-deleted individuals with schizophrenia." I say all this bearing in mind that plurality might be as much of a feature of schizophrenia (see here) as it is with autism (see here).

Although perhaps stretching the association a little, I am minded to bring in a few blog entries I've previously made about how the reported genetics and biology of schizophrenia might yield some more information about this Del22-SSD tie-up. Y'know, things like the much-discussed schizophrenia and microglia connection (see here) or the idea that markers of gluten sensitivity might show more than a passing connection to schizophrenia (see here). Continuing the theme of immune function being potentially linked to Del22, how about looking at various inflammatory markers in cases of Del22-SSD (see here) on the basis also that inflammation might have social cognition effects too (see here)? And finally, what about the suggestion that the use of fish oil supplementation might help prevent psychosis in 'at-risk' groups (see here)? The research list is potentially endless.

----------

[1] Vangkilde A. et al. Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population-A Nationwide Register Study. Schizophr Bull. 2016 Jan 5. pii: sbv195.

[2] Vorstman JA. et al. Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. JAMA Psychiatry. 2015 Apr;72(4):377-85.

[3] Monks S. et al. Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. Schizophr Res. 2014 Mar;153(1-3):231-6.

----------

Vangkilde, A., Olsen, L., Hoeffding, L., Pedersen, C., Mortensen, P., Werge, T., & Trabjerg, B. (2016). Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population—A Nationwide Register Study Schizophrenia Bulletin DOI: 10.1093/schbul/sbv195

Schizophrenia and the constant (immune) gardeners

"Immune clue to preventing schizophrenia" went the BBC headline, as the paper by Peter Bloomfield and colleagues [1] garnered some significant media interest recently specifically tied into their findings suggesting that: "neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms."

Based on the use of "second-generation radioligand [11C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis", researchers reported on 56 participants looking to record their microglial activity. Microglia, as I've talked about before, are something like the constant gardeners of our immune defences in their role as macrophages (big eaters of the immune system) of the brain and spinal cord. Bloomfield et al reported that some of the highest levels of microglia activity were seen in those participants diagnosed with schizophrenia. There also appeared to be something of a potentially important dose related relationship between microglial activity and those at ultra-high risk of psychosis too. Ergo: "Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity." Quite a nice write-up of the study can be read here.

It's not necessarily new news that immune activation and inflammatory processes may be part and parcel of at least some schizophrenia. I've covered the topic quite a few times on this blog (see here and see here for example). The novelty in the Bloomfield results is that researchers actually looked at neuroinflammation as being part of the process linked to excess immune activation in their cohort including people on the schizophrenia-psychosis spectrum.

Where next with this work? Well, replication - independent replication - is a must-have for this area and might also include some analysis of other more general circulating markers of inflammation such as C-reactive protein (CRP) and other pentraxins for example. That also the orchestra of immune-related chemicals that fall under the banner of cytokines (see here) might also be included in further work would also be a valuable scientific addition bearing in mind that not all schizophrenia/psychosis might be immune related: remember the schizophrenias (plural). I might also forward the idea that we might already have some clues as to the possible agents involved in such immune stimulation as per the interesting work looking at Toxoplasma gondii and some schizophrenia (see here).

With regards to the BBC and other media talking about possible treatments focused on some 'anti-inflammatory' action, this again is not new news as per reports such as the one by Friedrich [2]. With other psychiatric labels in mind also talking about inflammation as being part and parcel of pathology (see here) there may be a variety of anti-inflammatory strategies requiring scientific analysis within the context of schizophrenia and/or psychosis. Indeed, such work might overlap across various different labels (see here) and even point to some rather unorthodox intervention ideas (see here and see here).

The times are a changin' for psychiatry methinks.

Music: All I Wanna Do Is Have Some Fun...

----------

[1] Bloomfield PS. et al. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. American Journal of Psychiatry. 2015. Oct 16.

[2] Friedrich MJ. Research on Psychiatric Disorders Targets Inflammation. JAMA. 2014; 312: 474-476.

----------

Bloomfield, P., Selvaraj, S., Veronese, M., Rizzo, G., Bertoldo, A., Owen, D., Bloomfield, M., Bonoldi, I., Kalk, N., Turkheimer, F., McGuire, P., de Paola, V., & Howes, O. (2015). Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [ C]PBR28 PET Brain Imaging Study American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.14101358

Immunosuppression as a therapeutic pathway of clozapine?

"Our data suggest that the superior therapeutic effect of clozapine may be a result of its presently shown immunosuppressive action."

So said the findings reported by Markus Larsson and colleagues [1] (open-access available here) who set about investigating "the effects of chronic treatment with antipsychotic drugs on brain levels of cytokines and KYNA [kynurenic acid]" in a rat model. The rationale for the study came in part from the idea that schizophrenia (or least some schizophrenia) may show more than a passing connection to a state of inflammation (see here) as well as a link to the kynurenine pathway (see here). Whether or not antipsychotic medication might show some 'effect' on these processes is still a little up in the air.

Then: "Rats were treated daily by intraperitoneally administered haloperidol (1.5 mg/kg, n = 6), olanzapine (2 mg/kg, n = 6), and clozapine (20 mg/kg, n = 6) or saline (n = 6) for 30 days." Kynurenic acid (KYNA) in brain tissue and levels of various cytokines (chemical messengers of the immune system) in cerebrospinal fluid (CSF) were assayed for among the various groups in comparison to a control group of animals receiving saline.

"Clozapine, but not haloperidol or olanzapine-treated rats displayed significantly lower cerebrospinal fluid (CSF) levels of interleukin-8 compared to controls." This is an interesting finding that needs to be treated with some caution given that aside from IL-8 all other cytokines were reported as being below the limits of detection of the analytical methods employed. Interleukin-8 (IL-8) is normally considered to be a pro-inflammatory cytokine specifically associated with acute inflammation [2]. With schizophrenia in mind, IL-8 has been tied into the whole maternal immune activation (MIA) theory of schizophrenia as per data such as those reported by Alan Brown and colleagues [3]. Brown et al reported on: "a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring." More directly, IL-8 levels in relation to 'some' schizophrenia [4] have been reported in the research literature.

That rats treated with clozapine showed a lower level of IL-8 than following use of the other antipsychotics has been translated by the authors as possible evidence that clozapine may have an immunosuppressive action. Granted we don't have 'before and after' data in the Larsson study so we have to be a little careful about generalisation but I do find this to be a tantalising prospect. Whilst it might not be new news to some readers that clozapine might be doing quite a bit more than we expected when it comes to its use in a condition like schizophrenia, the idea that immune function might be 'affected' by administration [5] is a new one for me. A quick survey of some of the other literature on the immuno-modulatory aspects to clozapine indeed reveals that there is something to see here. Chen and colleagues [6] for example, talked about the anti-inflammatory possibilities attached to something like clozapine.

Within the various discussions about how several psychiatric labels might have an important 'inflammatory' component behind them (see here) it's not outside of the realms of possibility that the other pharmacological actions of the drug might also be complemented by such immunological alterations too. This might be a bit of a double-edged sword insofar as working out a more targeted 'use' for the drug whilst at the same time realising how complex the immune system truly is and why we should be cautious about tinkering too much with it.

Music: Passenger - I'll Be Your Man.

----------

[1] Larsson MK. et al. Chronic Antipsychotic Treatment in the Rat - Effects on Brain Interleukin-8 and Kynurenic Acid. Int J Tryptophan Res. 2015 Sep 20;8:49-52.

[2] Harada A. et al. Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol. 1994 Nov;56(5):559-64.

[3] Brown AS. et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004 May;161(5):889-95.

[4] Zhang XY. et al. Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res. 2002 Oct 1;57(2-3):247-58.

[5] Røge R. et al. Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? Schizophr Res. 2012 Sep;140(1-3):204-13.

[6] Chen ML. et al. Regulation of macrophage immune responses by antipsychotic drugs. Immunopharmacol Immunotoxicol. 2013 Oct;35(5):573-80.

----------

Larsson MK, Schwieler L, Goiny M, Erhardt S, & Engberg G (2015). Chronic Antipsychotic Treatment in the Rat - Effects on Brain Interleukin-8 and Kynurenic Acid. International journal of tryptophan research : IJTR, 8, 49-52 PMID: 26448689

The bipolar - schizoaffective - schizophrenia spectrum?

"This pattern of results is consistent with the conceptualisation of a spectrum of disorders, ranging from BDP [bipolar disorder] at one end, to SAD [schizoaffective disorder] in the middle, and SCZ [schizophrenia] at the other end." So concluded the paper by Serafino Mancuso and colleagues [1] examining clinical data derived from the Australian Survey of High Impact Psychosis (SHIP).

The thing about perfection is that it's unknowable.

I'm not going to dwell too long on this paper aside from suggesting that such results add to a growing trend in psychiatry asking whether our current compartmentalising way of diagnosing mental health issues is actually fit for purpose à la RDoC (Research Domain Criteria). A few weeks back Virginia Hughes talked about 'Category Fail' based to a large extent on the paper by London [2] who suggested that: "The use of autism as a diagnostic category guiding translational research is fraught with so many problems that the validity of research conclusions is suspect." Sentiments which have been rumbling on for quite a few years now.

The Mancuso results are complemented by quite a few other findings suggestive of fuzzy boundaries when it comes to giving psychiatric labels and their associated qualities. Plucking randomly from the peer-reviewed literature, the paper from Silver & Bilker [3] for example, talking about people with schizophrenia showing "impairments in [the] recognition of identity and emotional facial clues" as part of social cognition carries hints of what has been described in cases of autism for example. The findings reported by Langdon and colleagues [4] talking about a specific Theory of Mind (ToM) impairment in their cohort with early psychosis provides further evidence for the non-exclusivity of this concept when similarly talked about with autism in mind (see here). I might add that I'm not a great fan of the link between ToM and autism anyway.

Of course, one might also see the concept of a spectrum of psychiatric conditions to be itself rather too simplified when it comes to describing and categorising behaviours and actions. The growing pluralisation of autism - 'the autisms' - and schizophrenia - 'the schizophrenias' - perhaps implies that 'tapestry' might be a better way to define presented symptoms, bearing in mind the potential number of permutations of displayed symptoms and underlying genetic/biological issues that may be evident. It might also cover the evidence talking about overlapping spectrums also.

It's all getting rather complicated...

Music: Chase & Status - Lost & Not Found.

----------

[1] Mancuso SG. et al. A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. J Affect Disord. 2014 Sep 30;172C:30-37.

[2] London EB. Categorical diagnosis: a fatal flaw for autism research? Trends Neurosci. 2014 Nov 14;37(12):683-686.

[3] Silver H. & Bilker WB. Social cognition in schizophrenia and healthy aging: Differences and similarities. Schizophr Res. 2014 Nov 15;160(1-3):157-162.

[4] Langdon R. et al. Theory of mind and neurocognition in early psychosis: a quasi-experimental study. BMC Psychiatry 2014, 14:316

----------

Mancuso SG, Morgan VA, Mitchell PB, Berk M, Young A, & Castle DJ (2014). A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. Journal of affective disorders, 172C, 30-37 PMID: 25451392

Folate receptor autoantibodies and (some) schizophrenia

I am the league's director, Silas Ramsbottom.

Upon reading the paper published by Ramaekers and colleagues [1] talking about the use of folinic acid in cases of schizophrenia as a function of the presence of "Auto-antibodies against folate receptor alpha (FRα)", I raised a little smile. Not only because the authors suggested that there may be quite a lot more to see in this area on top of some already interesting discussions about the folate cycle and schizophrenia, but also because of the 'overlap' with some autism findings which have been previously discussed on this blog (see here). Indeed, if readers would like quite a nice summary of this area of investigation - folate receptor autoantibodies - I'm minded to direct them to the paper by Richard Frye and colleagues [2] (open-access) which initially presented the idea of cerebral folate receptor autoantibodies occurring in autism to the world and was the source material for that previous blog post.

Quoting from the Ramaekers study text: "Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls". This was a study of those described as having "schizophrenia unresponsive to conventional treatment" and alongside the presence of those autoantibodies, researchers also assessed what some of the metabolic knock-on effects might have been in terms of analysis of spinal fluid levels of "MTHF [5,10-Methylenetetrahydrofolate] and the metabolites of pterins, dopamine and serotonin". It appears that FR autoantibodies may indeed affect levels of said compounds alongside "intermediates linked to metabolic processes affecting homocysteine levels... [and] synthesis of tetrahydrobiopterin". Homocysteine and tetrahydrobiopterin (BH4) in schizophrenia y'say?

"Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement." Without wishing to provide any medical or clinical advice on the utility of folinic acid for schizophrenia or anything else, these are interesting findings. This is not the first time that folinic acid has been discussed in the research literature with schizophrenia in mind as per the case report by Wang and colleagues [3]. In that single case, authors described the presence of the MTHFR mutation - "665C>T homozygous mutations in the MTHFR gene" - as the reason for secondary cerebral folate deficiency. Other authors have discussed more pertinent cases [4]. Obviously one would like to see more formal clinical trials on the use of folinic acid as potentially being appropriate for at least some of the [plural] schizophrenias. The important thing to take from the Ramaekers and other studies is that a panel of tests might be able to spot who might be best responders to this kind of intervention...

Music to close, and Peter Griffin sings the opening tune to Indiana Jones and The Last Crusade? Why not.

----------

[1] Ramaekers VT. et al. Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Mol Genet Metab. 2014 Oct 12. pii: S1096-7192(14)00311-4.

[2] Frye RE. et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry 2013;18(3):369-381. doi:10.1038/mp.2011.175.

[3] Wang Q. et al. Methylenetetrahydrofolate reductase deficiency-induced schizophrenia in a school-age boy. Zhongguo Dang Dai Er Ke Za Zhi. 2014 Jan;16(1):62-6.

[4] Ho A. et al. Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report. J Child Neurol. 2010 Jul;25(7):898-900.

----------

Ramaekers VT, Thöny B, Sequeira JM, Ansseau M, Philippe P, Boemer F, Bours V, & Quadros EV (2014). Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Molecular genetics and metabolism PMID: 25456743

One fifth of schizophrenia cases linked to Toxoplasma gondii?

"The PAF [population attributable fraction] for schizophrenia in those exposed to T. gondii is tentatively 21.4%". That was the headline conclusion made by Prof. Gary Smith [1] in his modelling analysis estimating what percentage of cases of schizophrenia might involve the protozoan Toxoplasma gondii. Some of the accompanying media about this potentially very important finding can be found here and here.

You don't need to study scaring, you just do it.

Although no expert on the PAF - defined as [2]: "the proportional reduction in average disease risk over a specified time interval that would be achieved by eliminating the exposure(s) of interest from the population while distributions of other risk factors in the population remain unchanged" - the author seems to have undertaken some nifty statistical analysis to calculate how many cases of schizophrenia might not occur if T. gondii infection wasn't present.

For those who might not be up to speed with this area, there is quite a bit of evidence to suggest that T. gondii infection (or history of infection) may well tie into the presentation of schizophrenia [3]. The evidence is not altogether straight-forward in this area [4] including some potential involvement for food (see a previous post), but there is certainly something more to see in this area of investigation and perhaps further in psychiatry. As I write this post, yet another study has found evidence of a possible link with schizophrenia in mind [5] and a meta-analysis [6]  has reported: "An increased seroprevalence of T. gondii IgM in patients with acute psychosis". I'll be coming back to that last paper in a subsequent post.

Prof. Smith has quite sensibly called for quite a bit more inspection of the possible connection between T. gondii infection and schizophrenia over and above just "ridiculing the idea of a connection". In the press release about his study he notes: "In other words, we ask, if you could stop infections with this parasite, how many cases could you prevent?” Smith said. “Over a lifetime, we found that you could prevent one-fifth of all cases. That, to me, is significant."

Knowing what we are starting to know about schizophrenia, it's direct and indirect impact on a person and the all-important possibility of plurality issues, I would have to agree that some priority be given to this line of thought albeit in conjunction with other factors undoubtedly moderating any relationship.

And since we're on the topic of organisms potentially affecting human behaviour, I'll draw your attention to a recent paper by Robert Yolken and colleagues [7] (a veteran of the T. gondii - schizophrenia research correlation) on Chlorovirus ATCV-1 and cognitive functions...

Music to close: Marina and the Diamonds with Primadonna.

----------

[1] Smith G. Estimating the population attributable fraction for schizophrenia when Toxoplasma gondii is assumed absent in human populations. Preventive Veterinary Medicine. 2014. October 23.

[2] Rockhill B. et al. Use and misuse of population attributable fractions. Am J Public Health. 1998 January; 88(1): 15–19.

[3] Torrey EF. et al. Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull. 2012 May;38(3):642-7.

[4] Li Y. et al. Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel. Schizophr Res. 2013 Dec;151(1-3):36-42.

[5] Khademvatan S. et al. Toxoplasma gondii Exposure and the Risk of Schizophrenia. Jundishapur Journal of Microbiology. 2014 November; 7(11): e12776.

[6] Monroe JM. et al. Meta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis. Schizophr Bull. 2014 Nov 9. pii: sbu159.

[7] Yolken RH. et al. Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice. Proc Natl Acad Sci U S A. 2014 Oct 27. pii: 201418895.

----------

Smith, G. (2014). Estimating the population attributable fraction for schizophrenia when Toxoplasma gondii is assumed absent in human populations Preventive Veterinary Medicine DOI: 10.1016/j.prevetmed.2014.10.009

More gluten sensitivity and schizophrenia

Dude means a regular sort of person...

"Our study in 100 people with schizophrenia compared to 100 matched controls replicates a higher prevalence of gluten sensitivity and higher mean antigliadin IgG antibody levels [in] schizophrenia".

So said one of the conclusions of the paper by Jessica Jackson and colleagues [1] as the results further stack up implicating immune function and diet in relation to at least some cases of schizophrenia. That being said, researchers did not find any "robust clinical profile" which differentiated those with antibodies from those without on the basis of symptom presentation, so it seems the only way to determine possible gluten sensitivity is to do some blood work.

I'd only be repeating myself (see here) if I went on discussing the Jackson results in any great detail. That such findings, alongside quite a lot more focus on the gut-brain axis (see here and see here) in relation to at least some schizophrenia (the schizophrenias?) are becoming all too frequent these days in the peer-reviewed research literature is deserving of some real action now. Indeed, a recent Nature piece said as much with the title: Gut–brain link grabs neuroscientists (perhaps only missing out on what exactly has been grabbed).

This authorship group have previously described preliminary results based on the use of a gluten-free diet in cases of schizophrenia [2] (open-access) but a large comprehensive trial is still lacking at the time of writing. Indeed one has to go back to 1986 and the days of Billy Ocean talking about The Tough Gettin' Going and the results published by Vlissides and colleagues [3] to see how long such a trial has been awaited (assuming we don't count the even earlier writings of the late Curt Dohan on this topic).

Oh and that a gluten-free diet might not be the only research direction to take is another potentially important point...

----------

[1] Jackson J. et al. Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. Schizophrenia Research. 2014. 11 October.

[2] Jackson J. et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr Res. 2012 Sep;140(1-3):262-3.

[3] Vlissides DN. et al. A double-blind gluten-free/gluten-load controlled trial in a secure ward population. Br J Psychiatry. 1986 Apr;148:447-52.

----------

Jackson J, Eaton W, Cascella N, Fasano A, Santora D, Sullivan K, Feldman S, Raley H, McMahon RP, Carpenter WT Jr, Demyanovich H, & Kelly DL (2014). Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. Schizophrenia research PMID: 25311778